Small Cell Lung Cancer Treatment (PDQ®)

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General Information About Small Cell Lung Cancer

Small cell lung cancer (SCLC) accounts for approximately 15% of bronchogenic carcinomas.

At the time of diagnosis, approximately 30% of patients with SCLC will have tumors confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited-stage disease (LD). Patients with tumors that have spread beyond the supraclavicular areas are said to have extensive-stage disease (ED).

SCLC is more responsive to chemotherapy and radiation therapy than other cell types of lung cancer; however, a cure is difficult to achieve because SCLC has a greater tendency to be widely disseminated by the time of diagnosis.

Incidence and Mortality

The overall incidence and mortality rates of SCLC in the United States have decreased during the past few decades.

Estimated new cases and deaths from lung cancer (SCLC and non-small cell lung cancer [NSCLC] combined) in the United States in 2014:

New cases: 224,210.

Deaths: 159,260.

Clinical Features

Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough, shortness of breath, and dyspnea. Other presenting symptoms include the following:

Chest pain.

Hoarseness.

Malaise.

Anorexia.

Weight loss.

Hemoptysis.

Symptoms may result from local invasion or compression of adjacent thoracic structures, such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck. Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases.

Infrequently, patients with SCLC may present with symptoms and signs of one of the following paraneoplastic syndromes:

Diagnosis

Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient. Investigations of patients with suspected SCLC focus on confirming the diagnosis and determining the extent of the disease.

The procedures used to determine the presence of cancer include the following:

History.

Physical examination.

Routine laboratory evaluations.

Chest x-ray.

Chest computed tomography scan with infusion of contrast material.

Biopsy.

Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC. Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

Prognosis and Survival

Regardless of stage, the current prognosis for patients with SCLC is unsatisfactory despite improvements in diagnosis and therapy made during the past 25 years. Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months. About 10% of the total population of SCLC patients remains free of disease during the 2 years from the start of therapy, which is the time period during which most relapses occur. Even these patients, however, are at risk of dying from lung cancer (both small and non-small cell types). The overall survival at 5 years is 5% to 10%.

An important prognostic factor for SCLC is the extent of disease. Patients with LD have a better prognosis than patients with ED. For patients with LD, median survival of 16 to 24 months and 5-year survivals of 14% with current forms of treatment have been reported. Patients diagnosed with LD who smoke should be encouraged to stop smoking before undergoing combined-modality therapy because continued smoking may compromise survival.

Improved long-term survival in patients with LD has been shown with combined-modality therapy.[Level of evidence: 1iiA] Although long-term survivors have been reported among patients who received either surgery or chemotherapy alone, chemotherapy combined with thoracic radiation therapy (TRT) is considered the standard of care. Adding TRT increases absolute survival by approximately 5% over chemotherapy alone. The optimal timing of TRT relative to chemotherapy has been evaluated in multiple trials and meta-analyses with the weight of evidence suggesting a small benefit to early TRT.[Level of evidence: 1iiA]

In patients with ED, median survival of 6 to 12 months is reported with currently available therapy, but long-term disease-free survival is rare.

Prophylactic cranial radiation prevents central nervous system recurrence and can improve survival in patients who have had a complete response to chemoradiation.[Level of evidence: 1iiA]

All patients with this type of cancer may appropriately be considered for inclusion in clinical trials at the time of diagnosis. Information about ongoing clinical trials is available from the NCI Web site.

Because of differences in clinical behavior, therapy, and epidemiology, these tumors are classified separately in the World Health Organization (WHO) revised classification. The variant form of SCLC called mixed small cell/large cell carcinoma was not retained in the revised WHO classification. Instead, SCLC is now described with only one variant, SCLC combined, when at least 10% of the tumor bulk is made of an associated non-small cell component.

SCLC presents as a proliferation of small cells with the following morphological features:

Scant cytoplasm.

Ill-defined borders.

Finely granular "salt and pepper" chromatin.

Absent or inconspicuous nucleoli.

Frequent nuclear molding.

A high mitotic count.

Combined small cell carcinoma includes a mixture of small cell and large cell or any other non-small cell component. Any cases showing at least 10% of SCLC are diagnosed as combined SCLC, and SCLC is limited to tumors with pure SCLC histology. SCLC associated with LCNEC is diagnosed as SCLC combined with LCNEC.

Nearly all SCLC are immunoreactive for keratin, thyroid transcription factor 1, and epithelial membrane antigen. Neuroendocrine and neural differentiation result in the expression of dopa decarboxylase, calcitonin, neuron-specific enolase, chromogranin A, CD56 (also known as nucleosomal histone kinase 1 or neural-cell adhesion molecule), gastrin-releasing peptide, and insulin-like growth factor 1. One or more markers of neuroendocrine differentiation can be found in approximately 75% of SCLC.

Although preinvasive and in situ malignant changes are frequently found in patients with non-small cell lung cancer, these findings are rare in patients with SCLC.

Limited-Stage Disease

No universally accepted definition of this term is available. Limited-stage disease (LD) SCLC is confined to the hemithorax of origin, the mediastinum, or the supraclavicular nodes, which can be encompassed within a tolerable radiation therapy port.

Patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from LD by various groups.

Extensive-Stage Disease

Extensive-stage disease (ED) SCLC has spread beyond the supraclavicular areas and is too widespread to be included within the definition of LD. Patients with distant metastases (M1) are always considered to have ED.

IASLC-AJCC TNM Staging System

The AJCC TNM defines LD as any T, except for T3-4, due to multiple lung nodals that do not fit in a tolerable radiation field, any N, and M0. This corresponds to TNM stages I to IIIB. Extensive disease is TNM stage IV with distant metastases (M1) including malignant pleural effusions.

The IASLC conducted an analysis of clinical TNM staging for SCLC using the sixth edition of the AJCC TNM staging system for lung cancer. Survivals for patients with clinical stages I and II disease are significantly different from those for patients with stage III disease with N2 or N3 involvement. Patients with pleural effusion have an intermediate prognosis between LD and ED with hematogenous metastases and will be classified as having M1 disease (or ED). Application of the TNM system will not change how patients are managed; however, the analysis suggests that, in the context of clinical trials in LD, accurate TNM staging and stratification may be important.

Staging Evaluation

Staging procedures for SCLC are important in distinguishing patients with disease limited to their thorax from those with distant metastases. At the time of initial diagnosis, approximately two-thirds of patients with SCLC have clinical evidence of metastases; most of the remaining patients have clinical evidence of extensive nodal involvement in the hilar, mediastinal, and sometimes supraclavicular regions.

Determining the stage of cancer allows an assessment of prognosis and a determination of treatment, particularly when chest radiation therapy or surgical excision is added to chemotherapy for patients with LD. If ED is confirmed, further evaluation should be individualized according to the signs and symptoms unique to the individual patient. Standard staging procedures include the following:

A thorough physical examination.

Routine blood counts and serum chemistries.

Chest and upper abdominal computed tomography (CT) scanning.

A radionuclide bone scan.

A brain magnetic resonance imaging scan or CT scan.

Bone marrow aspirate or biopsy in selected patients in which treatment would change based on the results.

The role of positron emission tomography (PET) is still under study. SCLC is fluorodeoxyglucose (FDG) avid at the primary site and at metastatic sites. PET may be used in staging patients with SCLC who are potential candidates for the addition of thoracic radiation therapy to chemotherapy, as PET may lead to upstaging or downstaging of patients and to alteration of radiation fields resulting from the identification of additional sites of nodal metastases.

Evidence (FDG-PET):

In a study of 120 patients with LD SCLC or ED SCLC, ten patients were upstaged and three patients were downstaged. PET was more sensitive and specific than CT scans for nonbrain distant metastases.

In a small series of 24 patients with LD by conventional staging, two patients were upstaged to ED. Unsuspected nodal metastases were documented in 25% of patients, which altered the radiation plan in these patients. At this time, sensitivity, specificity, and positive- or negative-predictive value of PET scanning and its enhancement of staging accuracy are uncertain.

Treatment Option Overview for Small Cell Lung Cancer

Chemotherapy and radiation therapy have been shown to improve survival for patients with small cell lung cancer (SCLC).

Chemotherapy

Chemotherapy improves the survival of patients with limited-stage disease (LD) or extensive-stage disease (ED), but it is curative in only a minority of patients. Because patients with SCLC tend to develop distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, rarely produce long-term survival. With incorporation of current chemotherapy regimens into the treatment program, however, survival is prolonged, with at least a fourfold to fivefold improvement in median survival compared with patients who are given no therapy.

The combination of platinum and etoposide is the most widely used standard chemotherapeutic regimen.[Level of evidence: 1iiA] No consistent survival benefit has resulted from platinum versus nonplatinum combinations, increased dose intensity or dose density, altered mode of administration (e.g., alternating or sequential administration) of various chemotherapeutic agents, or maintenance chemotherapy.[Level of evidence: 1iiA]

Radiation Therapy

SCLC is highly radiosensitive and thoracic radiation therapy improves survival of patients with LD and ED tumors.[Level of evidence: 1iiA] Prophylactic cranial radiation prevents central nervous system recurrence and may improve the long-term survival of patients who have responded to chemoradiation therapy [Level of evidence: 1iiA] and offers palliation of symptomatic metastatic disease.

Treatment for patients with limited-stage, extensive-stage, or recurrent SCLC is summarized in Table 1.

Despite treatment advances, the majority of patients with SCLC die of their tumor even with the best available therapy. Most of the improvements in the survival of patients with SCLC are attributable to clinical trials that have attempted to improve on the best available and most accepted therapy. Patient entry into such studies is highly desirable.

Information about ongoing clinical trials is available from the NCI Web site.

Chemotherapy and radiation therapy

Combined-modality treatment with etoposide and cisplatin with thoracic radiation therapy (TRT) is the most widely used treatment for patients with limited-stage disease (LD) SCLC.

Evidence (combined modality treatment):

Survival. The following results have been reported in clinical trials:
Mature results of prospective randomized trials suggest that combined-modality therapy produces a modest but significant improvement in survival of 5% at 3 years compared with chemotherapy alone.[Level of evidence: 1iiA]Clinical trials have consistently achieved median survivals of 18 to 24 months and 40% to 50% 2-year survival rates with less than a 3% treatment-related mortality.[Level of evidence: 1iiA]No consistent survival benefit has resulted from the following:[Level of evidence: 1iiA]
Increased dose intensity.Increased dose density.Administration of additional drugs.Altered modes of administration of various chemotherapeutic agents.Maintenance chemotherapy.

Length of treatment. The optimal duration of chemotherapy for patients with LD SCLC is not clearly defined, but no improvement exists in survival after the duration of drug administration exceeds 3 to 6 months. The preponderance of evidence available from randomized trials indicates that maintenance chemotherapy does not prolong survival for patients with LD SCLC.[Level of evidence: 1iiA]

Dose and timing. The optimal dose and timing of TRT remain controversial.
Multiple clinical trials and meta-analyses addressing the timing of TRT have been published, with the weight of evidence suggesting a small benefit to early TRT (i.e., TRT administered during the first or second cycle of chemotherapy administration).[Level of evidence: 1iiA]The amount of time from start to completion of TRT in LD SCLC may also effect overall survival (OS). In an analysis of four trials, the completion of therapy in less than 30 days was associated with an improved 5-year survival rate (relative risk, 0.62; 95% confidence interval, 0.49–0.80; P = .0003).[Level of evidence: 1iiA]Both once-daily and twice-daily chest radiation schedules have been used in regimens with etoposide and cisplatin. One randomized study showed a modest survival advantage in favor of twice-daily radiation therapy given for 3 weeks compared with once-daily radiation therapy to 45 Gy given for 5 weeks (26% vs. 16% at 5 years; P = .04).[Level of evidence: 1iiA] Esophagitis was increased with twice-daily treatment. Twice-daily radiation therapy has not been broadly adopted. Once-daily fractions to higher doses of greater than 60 Gy are feasible and commonly used; their clinical benefits are yet to be defined in phase III trials.[Level of evidence: 3iiiA]

Combination chemotherapy alone

Patients with a contraindication to radiation therapy could be treated with chemotherapy alone. Patients presenting with superior vena cava syndrome are treated immediately with combination chemotherapy, radiation therapy, or both, depending on the severity of presentation. (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.)

Surgery followed by chemotherapy or chemoradiation therapy

The role of surgery in the management of patients with SCLC is unproven. Small case series and population studies have reported favorable outcomes for the minority of LD patients with very limited disease, with small tumors pathologically confined to the lung of origin or the lung and ipsilateral hilar lymph nodes from surgical resection with adjuvant chemotherapy.[Level of evidence: 3iiiDii] Patients who have undergone surgery and then been diagnosed with SCLC generally receive adjuvant chemotherapy with or without radiation therapy. In patients who receive chemotherapy with radiation therapy, there is no improvement in survival with the addition of surgery.[Level of evidence: 3iiiDii] Given the absence of data from randomized trials, the role of surgery in the management of individual patients with SCLC must be considered, both in terms of potential benefit and risk from the surgical procedure.

Evidence (role of surgery):

A randomized study evaluating the role of surgery in addition to chemoradiation therapy enrolled 328 patients with LD SCLC and found no OS benefit with the addition of pulmonary resection.[Level of evidence: 1iiA]

Prophylactic cranial irradiation (PCI)

Patients who have achieved a complete remission can be considered for administration of PCI. Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system (CNS) metastases within 2 to 3 years after starting treatment. The majority of these patients relapse only in their brain, and nearly all of those who relapse in their CNS die of their cranial metastases. The risk of developing CNS metastases can be reduced by more than 50% by the administration of PCI.

Evidence (role of PCI):

A meta-analysis of seven randomized trials evaluating the value of PCI in patients in complete remission reported improvement in brain recurrence, disease-free survival, and OS with the addition of PCI. The 3-year OS was improved from 15% to 21% with PCI.[Level of evidence: 1iiA]

A randomized study (RTOG-0212) of 720 patients with LD SCLC in complete remission after chemoradiation therapy demonstrated that standard-dose PCI (25 Gy in 10 fractions) was as effective as and less toxic than higher doses of brain radiation.

Randomized trials such as EORTC-22003-08004 (NCT00005062) showed that doses higher than 25 Gy in 10 daily fractions do not improve long-term survival.

Neurologic sequelae

Retrospective studies have shown that long-term survivors of SCLC (>2 years from the start of treatment) have a high incidence of CNS impairment. Prospective studies have shown that patients treated with PCI do not have significantly worse neuropsychological function than patients not treated. The majority of patients with SCLC have neuropsychological abnormalities present before the start of PCI and have no detectable decline in their neurological status for as long as 2 years after the start of their PCI. Patients treated for SCLC continue to have declining neuropsychologic function after 2 years from the start of treatment. Additional neuropsychologic testing of patients beyond 2 years from the start of treatment will be needed before concluding that PCI does not contribute to the decline in intellectual function.

Treatment options for older patients

The optimal therapeutic approach in older patients remains unclear. A population analysis showed that increasing age was associated with a decreased performance status and increased comorbidity. Older patients were less likely to be treated with combined chemoradiation therapy, more intensive chemotherapy, and PCI. Older patients were also less likely to respond to therapy and had poorer survival outcomes. Whether this was a result of age and its associated comorbidities or suboptimal treatment delivery remains uncertain.

No specific phase III trial in older patients with LD SCLC has been reported; however, three secondary analyses of two cooperative group trials have been published evaluating outcomes in patients aged 70 years or older. The survival outcomes for the older patients were identical to their younger counterparts in both trials. The older patients experienced more toxic effects, particularly hematologic, compared with younger patients. There was a significant increase in treatment-related mortality in the EST-3588 trial that compared etoposide and cisplatin with either once-daily or twice-daily radiation therapy (1% for patients aged <70 years vs. 10% for patients aged ≥70 years; P = .01). Because the older patients enrolled in these phase III trials may not be representative of LD SCLC patients in the general population, caution must be exercised in extrapolating these results to the general population of older patients.

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation for patients with LD SCLC include the following:

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with
limited stage small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al.: Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 24 (7): 1057-63, 2006.

Combination chemotherapy

Chemotherapy for patients with extensive-stage disease (ED) SCLC is commonly given as a two-drug combination of platinum and etoposide in doses associated with at least moderate toxic effects (as in limited-stage [LD] SCLC). Cisplatin is associated with significant toxic effects and requires fluid hydration, which can be problematic in patients with cardiovascular disease. Carboplatin is active in SCLC, is dosed according to renal function, and is associated with less nonhematological toxic effects.

Other regimens appear to produce similar survival outcomes but have been studied less extensively or are in less common use.

Doses and schedules used in current programs yield overall response rates of 50% to 80% and complete response rates of 0% to 30% in patients with ED.[Level of evidence: 1iiA]

Intracranial metastases from small cell carcinoma may respond to chemotherapy as readily as metastases in other organs.

Evidence (standard regimens):

Two meta-analyses evaluating the role of platinum combinations versus nonplatinum combinations have been published.
A Cochrane analysis did not identify a difference in 6-, 12-, or 24-month survival.A meta-analysis of 19 trials published between 1981 and 1999 showed a significant survival advantage for patients receiving platinum-based chemotherapy compared with those not receiving a platinum agent.[Level of evidence: 1iiA]

The Hellenic Oncology Group conducted a phase III trial comparing cisplatin and etoposide with carboplatin plus etoposide. The median survival was 11.8 months in the cisplatin arm and 12.5 months in carboplatin-treated patients.[Level of evidence: 1iiA] Although this difference was not statistically significant, the trial was underpowered to prove equivalence of the two treatment regimens in patients with either LD or ED.

Evidence (other combination chemotherapy regimens):

Irinotecan. Five trials and two meta-analyses have evaluated the combination of etoposide and cisplatin versus irinotecan and cisplatin. Only one of the trials showed the superiority of the irinotecan and cisplatin combination.[Level of evidence: 1iiA] Subsequent trials and the meta-analyses support that the regimens provide equivalent clinical benefit with differing toxicity profiles.[Level of evidence: 1iiA] Irinotecan and cisplatin regimens led to less grade 3 to 4 anemia, neutropenia, and thrombocytopenia but more grade 3 to 4 vomiting and diarrhea than etoposide and cisplatin regimens. Treatment-related deaths were comparable between the two groups.

Topotecan. In a randomized trial of 784 patients, the combination of oral topotecan given with cisplatin for 5 days was not found to be superior to etoposide and cisplatin. The 1-year survival rate was 31% (95% confidence interval [CI], 27%–36%) and was deemed to be noninferior, as the difference of -0.03 met the predefined criteria of no more than 10% absolute difference in 1-year survival.[Level of evidence: 1iiA]

Paclitaxel. No consistent survival benefit has resulted from the addition of paclitaxel to etoposide and cisplatin.

Evidence (duration of treatment):

The optimal duration of chemotherapy is not clearly defined, but no obvious improvement in survival occurs when the duration of drug administration exceeds 6 months.

No clear evidence is available from reported data from randomized trials that maintenance chemotherapy will improve survival duration.[Level of evidence: 1iiA] However, a meta-analysis of 14 published, randomized trials assessing the benefit of duration/maintenance therapy reported an odds ratio of 0.67 for both 1- and 2-year overall survival (OS) of 0.67 (95% CI, 0.56–0.79; P < .001 for 1-year OS and 0.53–0.86; P < .001 for 2-year OS). This corresponded to an increase of 9% in 1-year OS and 4% in 2-year OS.[Level of evidence: 1iiA]

Evidence (dose intensification):

The role of dose intensification in patients with SCLC remains unclear. Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival. A number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC. These studies have yielded conflicting results.
Four studies have shown that a modest increase in dose intensity (25%–34%) was associated with a significant improvement in survival with no compromise in quality of life (QOL).[Level of evidence: 1iiA]Two of three studies that examined combinations of the variables of interval, dose per cycle, and number of cycles showed no advantage.[Level of evidence: 1iiA]The European Organization for Research and Treatment of Cancer trial (EORTC-08923) reported a randomized comparison of standard-dose cyclophosphamide, doxorubicin, and etoposide given every 3 weeks for five cycles versus intensified treatment given at 125% of the dose every 2 weeks for four cycles with granulocyte colony-stimulating factor (G-CSF) support. The median dose intensity delivered was 70% higher in the experimental arm; the median cumulative dose was similar in both arms. There was no difference between treatment groups in median or 2-year survival.A randomized, phase III trial compared ifosfamide, cisplatin, and etoposide (ICE), which was given every 4 weeks, with twice weekly ICE with G-CSF and autologous blood support. Despite achieving a relative dose intensity of 1.84 in the dose-accelerated arm, there was no difference in response rate (88% vs. 80%, respectively), median survival (14.4 vs. 13.9 months, respectively), or 2-year survival (19% vs. 22%, respectively) for dose-dense treatment compared with standard treatment.[Level of evidence: 1iiA] Patients who received dose-dense treatment spent less time on treatment and had fewer episodes of infection.A randomized, phase II study of identical design reported a significantly better median survival for the dose-dense arm (29.8 vs. 17.4 months, respectively; P = .02) and 2-year survival (62% vs. 36%, respectively; P = .05). However, given the small study size (only 70 patients), these results should be viewed with caution.

Factors influencing treatment with chemotherapy

Performance status

More patients with ED SCLC have greatly impaired performance status at the time of diagnosis than patients with LD. Such patients have a poor prognosis and tolerate aggressive chemotherapy or combined-modality therapy poorly. Single-agent intravenous, oral, and low-dose biweekly regimens have been developed for these patients.

Prospective, randomized studies have shown that patients with a poor prognosis who are treated with conventional regimens live longer than those treated with the single-agent, low-dose regimens or abbreviated courses of therapy. A study comparing chemotherapy every 3 weeks with treatment given as required for symptom control showed an improvement in QOL in those patients receiving regular treatment.[Level of evidence: 1iiDii]

Other studies have tested intensive one-drug or two-drug regimens. A study conducted by the Medical Research Council demonstrated similar efficacy for an etoposide plus vincristine regimen and a four-drug regimen. The latter regimen was associated with a greater risk of toxic effects and early death but was superior with respect to palliation of symptoms and psychological distress.[Level of evidence: 1iiC] Studies comparing a convenient oral treatment with single-agent oral etoposide versus combination therapy showed that the overall response rate and OS were significantly worse in the oral etoposide arm.[Level of evidence: 1iiA]

Age

Subgroup analyses of phase II and phase III trials of SCLC patients by age showed that myelosuppression and doxorubicin-induced cardiac toxic effects were more severe in older patients than in younger patients and that the incidence of treatment-related death tended to be higher in older patients. About 80% of older patients, however, received optimal treatment, and their survival was comparable to that of younger patients. The standard chemotherapy regimens for the general population could be applied to older patients in good general condition (i.e., performance status of 0–1, normal organ function, and no comorbidity). There is no evidence of a difference in response rate, disease-free survival (DFS), or OS in older patients compared with younger patients.

Radiation therapy

Radiation therapy to sites of metastatic disease unlikely to be immediately palliated by chemotherapy, especially brain, epidural, and bone metastases, is a standard treatment option for patients with ED SCLC. Brain metastases are treated with whole-brain radiation therapy.

Chest radiation therapy is sometimes given for superior vena cava syndrome, but chemotherapy alone, with radiation reserved for nonresponding patients, is appropriate initial treatment. (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.)

Prophylactic cranial irradiation
(PCI)

Patients with ED treated with chemotherapy who have achieved a response can be considered for administration of PCI.

Evidence (PCI):

A randomized trial of 286 patients with response following four to six cycles of chemotherapy compared PCI versus no further therapy with symptomatic brain metastases.[Level of evidence: 1iiDThe cumulative risk of brain metastases within 1 year was 14.6% in the radiation group (95% CI, 8.3–20.9) and 40.4% in the control group (95% CI, 32.1– 48.6). Radiation was associated with an increase in median DFS from 12.0 weeks to 14.7 weeks and in median OS from 5.4 months to 6.7 months after randomization.The 1-year survival rate was 27.1% (95% CI, 19.4–35.5) in the radiation group and 13.3% (95% CI, 8.1–19.9) in the control group.Radiation had side effects but did not have a clinically significant effect on global health status.

Combination chemotherapy and radiation therapy

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation for patients with ED SCLC include the following:

New drug regimens.

Alternative drug doses and schedules.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with
extensive stage small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Pujol JL, Carestia L, Daurès JP: Is there a case for cisplatin in the treatment of small-cell lung cancer? A meta-analysis of randomized trials of a cisplatin-containing regimen versus a regimen without this alkylating agent. Br J Cancer 83 (1): 8-15, 2000.

Controlled trial of twelve versus six courses of chemotherapy in the treatment of small-cell lung cancer. Report to the Medical Research Council by its Lung Cancer Working Party. Br J Cancer 59 (4): 584-90, 1989.

Bozcuk H, Artac M, Ozdogan M, et al.: Does maintenance/consolidation chemotherapy have a role in the management of small cell lung cancer (SCLC)? A metaanalysis of the published controlled trials. Cancer 104 (12): 2650-7, 2005.

Recurrent Small Cell Lung Cancer Treatment

Standard treatment options for patients with recurrent SCLC include the following:

Chemotherapy.

Palliative therapy.

At the time of recurrence, many SCLC patients are potential candidates for further therapy.

Chemotherapy

Although second-line chemotherapy has been shown to produce tumor regression, responses are usually short lived; the median survival is rarely more than 12 months and usually less than 6 months after second-line therapy. Response to first-line chemotherapy predicts for subsequent response to second-line therapy.

As in other chemosensitive tumors (e.g., Hodgkin lymphoma and ovarian epithelial cancer), two main categories of patients receiving second-line chemotherapy have been described: sensitive and resistant. Sensitive patients have a first-line response that lasted more than 90 days after treatment was completed. These patients have the greatest benefit from second-line chemotherapy. Patients with sensitive disease respond to the same initial regimen in approximately 50% of cases; however, cumulative toxic effects may ensue. Resistant patients either did not respond to first-line chemotherapy or responded initially but relapsed within 90 days of completion of their primary therapy. Results from phase II studies of drugs such as topotecan, irinotecan, and gemcitabine indicate that response rates to agents vary depending on whether patients have sensitive, resistant, or refractory disease.[Level of evidence: 3iiiDii]

Topotecan is standard chemotherapy for recurrent SCLC. Patients with sensitive disease may achieve response to a number of agents including topotecan, irinotecan, taxanes, vinorelbine, paclitaxel, or gemcitabine.[Level of evidence: 3iiiDii] Response rates to combination agents are generally higher than those reported for single agents; however, many studies do not report the patients with sensitive, resistant, or refractory disease.

Evidence (topotecan):

A randomized comparison of second-line treatment with either cyclophosphamide, doxorubicin, and vincristine (CAV) or topotecan in patients with sensitive disease reported no significant difference in response rates or survival, but palliation of common lung cancer symptoms was better with topotecan.[Level of evidence: 1iiC]

A phase III trial comparing chemotherapy with best supportive care (BSC) in relapsed SCLC patients demonstrated that the addition of oral topotecan to BSC significantly increased overall survival and resulted in better symptom control compared with BSC alone.[Level of evidence: 1iiA] The study enrolled 141 patients with chemosensitive or chemoresistant relapsed SCLC who were unsuitable for further standard intravenous chemotherapy. The median survival times for patients receiving topotecan plus BSC were 25.9 weeks versus 13.9 weeks for BSC alone (P = .01).

A randomized, phase III trial (CWRU-SKF-1598) of 304 patients assessed the use of oral topotecan (2.3 mg/m2/day for 5 days every 21 days) or intravenous topotecan (1.5 mg/m2/day for 5 days every 21 days). Confirmed response rates were 18.3% and 21.9%, respectively.[Level of evidence: 1iiDii] Secondary endpoints of median survival and 1-year survival rates were also similar (33 weeks vs. 35 weeks and 33% vs. 29%, respectively). Patients receiving oral topotecan experienced less grade 4 neutropenia (47% vs. 64.2%) but more diarrhea of all grades (35.9% vs. 19.9%) than with intravenous topotecan. Quality-of-life (QOL) analysis (using a nonvalidated QOL questionnaire) demonstrated no significant difference between the two arms.

Palliative therapy

Patients with central nervous system (CNS) recurrences can often obtain palliation of symptoms with additional chemotherapy and/or radiation therapy. A retrospective review showed that 43% of patients treated with additional chemotherapy at the time of CNS relapse responded to second-line chemotherapy. The majority of patients treated with radiation therapy obtain objective responses and improvement following radiation therapy.

Some patients with intrinsic endobronchial obstructing lesions or extrinsic compression caused by the tumor have achieved successful palliation with endobronchial laser therapy (for endobronchial lesions only) and/or brachytherapy. Expandable metal stents can be safely inserted under local anesthesia via the bronchoscope, which results in improved symptoms and pulmonary function in patients with malignant airways obstruction.

Patients with progressive intrathoracic tumor after failing initial chemotherapy can achieve significant tumor responses, palliation of symptoms, and short-term local control with external-beam radiation therapy. Only the rare patient, however, will experience long-term survival following salvage radiation therapy.

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation for patients with recurrent SCLC include phase I and II clinical trials of new drugs.

Current Clinical Trials

General information about clinical trials is also available from the NCI Web site.

Ardizzoni A, Hansen H, Dombernowsky P, et al.: Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 15 (5): 2090-6, 1997.